Pathophysiological roles and pharmacological significance of small GTPases of the Ras superfamily

Development of 3D in vitro models for testing new pharmacological approaches and drug combinations

Research Description: Our studies focus on the physiological roles and pharmacological significance of small GTPases of the Ras superfamily. In particular, we are interested in how to target disorders where the Ras pathway is activated without direct oncogenic mutation of the Ras protein itself. While such activating changes in Ras are the most common oncogenic mutations in human cancer, the majority of cancers and many other hyperproliferative disorders have increased Ras signal transduction that is driven through other mechanisms. In recent years, our efforts have concentrated in the areas of Type 1 Neurofibromatosis (NF1) and breast cancer.

NF1 is the most frequent genetic cause of both tumors and neurological problems, with a birth incidence of about 1 in 3,000. Nearly all patients have benign neurofibromas, and there is increased risk of malignant peripheral nerve sheath tumors and other cancers. There is no effective current pharmacological treatment for these tumors. We have developed collaborative projects with the goal of the identification of non-toxic and mechanistically specific drugs for NF1 treatment. Our hypothesis is that increased activation of Ras signaling underlies the pathological development of NF1 and provides therapeutic targets.

Our work in breast cancer research is focused on the identification of new therapeutic approaches through the development and use of novel 3D in vitro models. We believe that this approach will provide more relevant results than are obtained from testing new drugs in conventional cell culture in 2D on plastic dishes, while being significantly more rapid and high-throughput than testing in animals. We are addressing two main problems: discovery of the factors that cause the progress from ductal carcinoma in situ (DCIS) to find how to block malignant progression; and identification of a viable targeted approach to triple-negative disease/basal-type breast cancer. We expect that the models and approaches that we are developing will address both of those challenges, and also be useful to other investigators who are tackling other important issues in breast cancer.